4-Oxy-cyclopent-2-en-1-one derivative, a prostaglandin intermediate, and the process for its preparation

ABSTRACT

Compounds of the general formula I are disclosed as useful intermediates in the preparation of prostanoids: ##STR1## wherein A represents O or H, OR z  ; 
     R z  represents hydrogen or a protecting group; 
     R x  represents hydrogen or a protecting group; and 
     R y  represents halogen, a substituted thio group, di-substituted amino group, or a group of the formula R 2 , and R 2  represents a straight-or branched-chain alkyl alkenyl or alkynyl group which may optionally be substituted by one or more carboxyl, carboxylic acid ester, or free or protected hydroxyl, thiol, aldehyde or keto groups; 
     with the provisos that R x  is not hydrogen when A is O and R y  is R 2  ; and that when A is H, OR z  R y  is R 2  and R x  and R z  are not both hydrogen. 
     Processes for the preparation of these compounds and of 2-substituted 4-hydroxy-cyclopent-2-en-1-one derivatives are also disclosed.

This is a continuation of application Ser. No. 070,920, filed Aug. 20,1979, now abandoned.

This invention relates to processes for the synthetic preparation ofcompounds of the prostaglandin group, including both naturally-occurringmembers and various modified analogues. These compounds are hereincollectively termed prostanoids (E. J. Corey, T. Ravindranathan, and S.Terashima, J. Am. Chem. Soc., 1971, 93, 4326).

Natural prostaglandins, exemplified by prostaglandin E₁ (14), are afamily of biologically-active lipids which are normal constituents ofanimal and human tissues, or are elaborated by these tissues in responseto various stimuli. Although present in very low concentrations, theyare believed to be involved in a wide variety of biological processes,including reproduction, muscle expansion and contraction, respiration,lipid metabolism, kidney function, central nervous system activity,gastric secretion, cardiovascular activity, immune response, andtemperature control. They have been the subject of extensive researchand review. (See for example, P. Crabbe (ed.), "Prostaglandin Research",Academic Press, New York, 1977; K. H. Gibson, Chem. Soc. Rev., 1977, 6,489; N. Kharasch and J. Fried (eds), "Biochemical Aspects ofProstaglandins and Thromboxanes", Academic Press, New York, 1977). Anumber of routes are available for the synthesis of prostaglandinsidentical in structure and configuration with the natural materials.(See for example, A. Mitra, "The Synthesis of Prostaglandins", Wiley andSons, New York, 1977; J. S. Bindra and R. Bindra, "ProstaglandinSynthesis", Academic Press, New York, 1977; P. Crabbe (ed),"Prostaglandin Research", Academic Press, New York, 1977).

Widespread therapeutic use of prostaglandins, derived either fromnatural sources or laboratory synthesis, has to date been hinderedprimarily by their rapid inactivation by metabolic processes in vivo andby their limited selectivity of action. Attempts to overcome thesedrawbacks have involved the synthesis of analogues with improvedmetabolic stability and improved selectivity compared to the naturalcompounds. (See for example, A. Mitra, "The Synthesis ofProstaglandins", Wiley and Sons, New York, 1977; J. S. Bindra and R.Bindra, "Prostaglandin Synthesis", Academic Press, New York, 1977; P.Crabbe (ed) "Prostaglandin Research", Academic Press, New York, 1977;Orth and H-E. Radunz, Top. Curr. Chem., 1977, 72, 51). Variation of thetwo side chains which are attached to the cyclic prostaglandin nucleushas been a promising approach in this regard.

Several prostanoids of natural and modified structure currently find usein clinical and veterinary practice [K. B. Mallion, in "AliphaticChemistry", ed. A. McKillop (Specialist Periodical Reports), TheChemical Society, London, 1977, Vol. 5, p. 240].

It is an object of the present invention to provide an improved processfor the preparation of prostanoids and novel intermediates preparedtherein.

The conversion of 2-substituted 4-hydroxycyclopent-2-en-1-onederivatives of the formula: ##STR2## into prostanoids by means ofconjugate addition reactions has been previously described. (See forexample, G. Stork and T. Takahashi, J. Am. Chem. Soc., 1977, 99 1275; C.J. Sih, J. B. Heather, R. Sood, P. Price, G. Peruzzotti, L. F. H. Leeand S. S. Lee, J. Am. Chem. Soc., 1975, 97, 865; C. J. Sih, R. G.Salomon, P. Price, R. Sood and G. Peruzzotti, J. Am. Chem. Soc., 1975,97, 857; F. S. Alvarez, D. Wren, and A. Price, J. Am. Chem. Soc., 1972,94, 7823; A. F. Kluge, K. G. Untch and J. H. Fried, J. Am. Chem. Soc.,1972, 94, 7827; A. F. Kluge, K. G. Untch, and J. H. Fried, J. Am. Chem.Soc., 1972, 94, 9256). By these conjugate addition reactions, eithernatural prostaglandins or a wide range of modified analogues thereof maybe prepared. It is a particular object of the present invention toprovide an improved process for the preparation of 2-substituted4-hydroxycyclopent-2-en-1-one derivatives of the above type, whereby aconvenient and efficient process for the preparation of prostanoids isprovided enabling ready access to the prostanoids either as opticallypure stereoisomers or as mixtures thereof. The preparation from commonintermediate compounds of either natural prostaglandins or a wide rangeof modified analogues thereof, is thus facilitated.

According to a first aspect of the present invention there are provided,as novel intermediates in the production of prostanoids, compounds ofthe general formula I: ##STR3## wherein A represents O or H, OR^(z) ;R^(z) represents hydrogen or a protecting group; R^(x) representshydrogen or a protecting group; and R^(y) represents halogen,particularly chlorine, bromine or iodine, a substituted thio group,particularly an alkyl thio group, a di-substituted amino group,particularly a di-alkyl amino group, or a group of the formula R², andR² represents a straight- or branched-chain alkyl, alkenyl or alkynylgroup for example of up to 10 carbon atoms, particularly of 4 to 10carbon atoms, which may optionally be substituted by one or morecarboxyl, carboxylic acid ester, or free or protected hydroxyl, thiol,aldehyde or keto groups; with the provisos that R^(x) is not hydrogenwhen A is O and R^(y) is R² ; and that when A is H, OR^(z), R^(y) is R²,and R^(x) and R^(z) are not both hydrogen.

As used throughout this specification, the term "protecting group" isused to denote a removable protective group for an alcoholic hydroxylgroup. Such groups are well known and include, for example, substitutedsilyl groups, alkoxyalkyl groups, a tetrahydrofuran-2-yl group and atetrahydropyran-2-yl group.

Preferably, the protecting group represented by R^(z) is an alkoxyalkylgroup such as an ethoxyethyl group, a tetrahydrofuran-2-yl group or atetrahydropyran-2-yl group. Preferably also, the protecting grouprepresented by R^(x) is a silyl group tri-substituted with alkyl and/oraryl residues, for example, a dimethyl-t-butylsilyl group.

The carboxylic acid ester groups which may be optional substituents onthe R² chain include, for example, the lower alkyl esters. The protectedhydroxy or thiol groups which similarly may be optional substituentsinclude ethers and their thio analogues for example, lower alkyl ethersand thio-ethers and hydroxy groups protected with protecting groups suchas substituted silyl groups, alkoxyalkyl groups, a tetrahydrofuran-2-ylgroup or a tetrahydropyran-2-yl group. The protected aldehyde or ketogroups which may also be optional substituents include non-cyclic andcyclic acetals or ketals and their thio analogues.

According to a further aspect of this invention there is provided aprocess for the preparation of compounds of the general formula I asdefined above wherein A represents O, which comprises:

(a) partial dehalogenation of a compound of the general formula II:##STR4## wherein Hal represents halogen and R^(x) is as defined above,to produce a compound of the general formula Ia: ##STR5## wherein Haland R^(x) are as defined above; and, if desired, total or partialinversion of the hydroxyl or protected hydroxyl substituent;

(b) protection of the hydroxyl substituent of a compound of the generalformula Ia as defined above in which R^(x) represents hydrogen toproduce a compound of the general formula Ib: ##STR6## wherein Hal is asdefined above and R¹ represents a protecting group; and, if desired,total or partial inversion of the protected hydroxyl substituent;

(c) replacement of the halogen substituent of a compound of the generalformula Ib as defined above, to produce a compound of the generalformula Ic: ##STR7## wherein R⁴ represents a substituted thio group or adisubstituted amino group and R¹ represents a protecting group; and, ifdesired, total or partial inversion of the protected hydroxylsubstituent; and

(d) reaction of a compound of the general formula Ib as defined above orof a compound of the general formula Ic as defined above in a conjugateaddition-elimination reaction to produce a compound of the generalformula Id: ##STR8## wherein R¹ represents a protecting group and R² isas defined above, and, if desired, total or partial inversion of theprotected hydroxyl substituent.

Preferably, said compound of the general formula II is prepared byoxidative decarboxylation of a compound of the general formula IIa:##STR9## wherein Hal represents a halogen and R^(x) is as defined inclaim 1; if desired, protection of the hydroxyl substituent of acompound of the general formula IIa in which R^(x) represents hydrogen;and, if desired, total or partial inversion of the hydroxyl or protectedhydroxyl substituent.

Preferably also, said compound of the general formula IIa is prepared byring-contraction of phenol or 2,4,6-trihalophenol with a halogen in thepresence of an alkali.

If desired, the process of this aspect may also include the step oftotal or partial resolution of a racemic mixture of a compound of thegeneral formula Ia, Ib, Ic, Id, II or IIa. In addition, the process mayalso include the step of modification of the group represented by R² orof addition, replacement or modification of an optional substituent onthe group represented by R² in a compound of the general formula Id.

According to a further aspect of this invention, there is provided aprocess for the preparation of compounds of the general formula I asdefined above wherein A represents H, OR^(z) and R^(y) represents R²,which comprises:

(a) reduction of a compound of the general formula Id: ##STR10## whereinR¹ represents a protecting group and R² is as defined above to produce acompound of the general formula Ie ##STR11## wherein R¹ represents aprotecting group and R² is as defined above; and if desired, total orpartial inversion of the configuration of the hydroxyl substituent;

(b) protection of the free hydroxyl substituent of a compound of thegeneral formula Ie as defined above to produce a compound of the generalformula If ##STR12## wherein R¹ represents a protecting group, R³represents a protecting group and R² is as defined above; and ifdesired, total or partial inversion of the configuration of the --OR³substituent; and

(c) selective removal of the R¹ protecting group of a compound of thegeneral formula If as defined above to produce a compound of the generalformula Ig ##STR13## wherein R³ represents a protecting group and R² isas defined above; and, if desired, total or partial inversion of theconfiguration of the --OR³ substituent.

The process of this aspect may also include the step of total or partialresolution of a racemic mixture of the compound of the general formulaIe, If or Ig. In addition, the process may also include the step ofmodification of the group represented by R² in a compound of the generalformula Ie, If or Ig.

According to yet another aspect of this invention, there is provided aprocess for the preparation of compounds of the general formula III:##STR14## wherein R² represents a straight- or branched-chain alkyl,alkenyl or alkynyl group which may optionally be substituted by one ormore carboxyl, carboxylic acid ester, or free or protected hydroxy,thiol, aldehyde or keto groups; and R^(z) represents hydrogen or aprotecting group; which comprises:

(a) when R^(z) represents a protecting group; oxidation of the freehydroxyl group of a compound of the general formula Ig: ##STR15##wherein R³ represents a protecting group and R² is as defined above, toproduce a compound of the general formula IIIa: ##STR16## wherein R³represents a protecting group and R² is as defined above; and ifdesired, total or partial inversion of the configuration of theprotected hydroxyl substituent; and

(b) when R^(z) represents hydrogen, removal of the protecting group of acompound of the general formula IIIa as defined above, to produce acompound of the general formula IIIb: ##STR17## wherein R² is as definedabove; and, if desired, total or partial inversion of the configurationof the hydroxyl substituent.

It is a particular feature of the present invention that the partialdehalogenation of the compounds of formula II leads to compounds offormulae Ib and Ic, which undergo highly efficient addition-eliminationreactions to form the compounds of formula Id.

As noted above, prostanoids have been prepared from compounds of thegeneral formula III and, if desired, the R^(z) protecting group may beremoved or replaced by an alternative protecting group prior toconversion of the compounds of general formula III into prostanoids.

It will be appreciated that the various compounds referred to throughoutthis specification are chiral and the present invention relates both tothe individual stereoisomers and to any mixtures thereof whether thesemixtures include enantiomers and/or diastereoisomers. In accordance withaccepted nomenclature, the dotted lines used in the formulae throughoutthis specification indicate that the attached group lies behind thegeneral plane of the ring system, i.e., that the group is in anα-configuration; whilst thickened lines indicate that the attached grouplies in front of the general plane of the system, i.e., that the groupis in a β-configuration. The wavy lines used in the formulae throughoutthis specification indicate that the attached group is present in an α-or β-configuration or is present in both α- and β-configurations, thusincluding not only all the individual stereoisomers thereof, but alsoall mixtures of such stereoisomers, including optically inactive racemicmixtures of enantiomers and optically active mixtures in which oneenantiomer is present in excess relative to the other enantiomer, aswell as mixtures of diastereoisomers.

It will be appreciated from the above general description and from thefurther description hereinafter that the present invention providesseveral advantages including:

(i) the ready accessibility of prostanoids either as optically purestereoisomers or as mixtures thereof;

(ii) the preparation from common intermediates of either naturalprostaglandins or a wide range of modified analogues;

(iii) the preparation of the common intermediates for the synthesis ofprostanoids from a cheap, readily available starting material;

(iv) processes which are convenient to carry out and efficient in theirsynthetic yields;

(v) processes which permit the facile introduction of isotopic labels incertain stages, the resulting labelled prostanoids being of value inbiological studies.

Formulae (1) to (20) referred to in the following detailed descriptionof preferred processes and compounds of the present invention are setout on the following pages.

Both naturally-occurring prostaglandins and modified analogues,collectively termed prostanoids, can be prepared from the known racemic(1R*, 4R*)-3,5,5-trichloro-1,4-dihydroxycyclopent-2-ene-1-carboxylicacid (3) (R. M. Christie, R. W. Rickards, K. J. Schmalzl and D. Taylor,Aust.J.Chem., 1977, 30, 2195; A. W. Burgstahler, T. B. Lewis, and M. O.Abdel-Rahman, J. Org. Chem., 1966, 31, 3516; C. J. Moye and S.Sternhell, Aust. J. Chem., 1966, 19, 2107). This acid (3) can itself beprepared from phenol (1) or 2,4,6-trichlorophenol (2) by the knownreaction involving ring-contraction with chlorine in the presence of analkali.

For the preparation of racemic prostanoids, the racemic acid (3) can beused as such without resolution into its enantiomers. For thepreparation of stereochemically pure prostanoids, the racemic acid (3)can be resolved into its enantiomers (4) and (5) by suitable methodsknown in the art, for example by the use of an optically active basewhich yields separable diastereoisomeric salts from which the twoenantiomeric acids (4) and (5) may be recovered. Alternatively, for thepreparation of stereochemically pure prostanoids, the racemic acid (3)may be used and a racemic compound produced from it in the syntheticsequence may be totally resolved into its individual enantiomers.Partial resolution at any stage will produce mixtures in which oneenantiomer is present in excess relative to the other.

The process leading to stereochemically pure prostanoids will bedescribed in detail for the resolved enantiomer (4) of the racemic acid(3). ##STR18## It will be clear to people skilled in the art, however,that resolution may be effected at a later stage, or that the processmay be carried out with partial or no resolution.

Oxidative decarboxylation of the (1R, 4R)-enantiomer (4) of the racemicacid (3) yields the (4R)-3,5,5,-trichloro-4-hydroxycyclopent-2-en-1-one(6), this reaction being known in the literature for the correspondingracemic compounds (R. Effenberger and R. W. Rickards, Aust. J. Chem.,1975, 28, 2731). The trichloro-enone (6) can be partially dechlorinatedby certain reducing agents to(4S)-3-chloro-4-hydroxycyclopent-2-en-1-one (7). Protection of thehydroxyl function of the chloro-enone (7) with a suitable group R¹,which is stable to the ensuing reaction conditions but which can beselectively removed when necessary, yields derivatives (8) of(4S)-3-chloro-4-hydroxycyclopent-2-en-1-one which are versatilesynthetic intermediates.

These chloro-enone derivatives (8), or the corresponding compoundsresulting from replacement of the 3-chloro substituent by a differenthalogen or a substituted thio or di-substituted amino group, undergofacile conjugate addition-elimination reactions with certainorganometallic species. Copper-mediated reactions involvingorganomagnesium or organolithium reagents are particularly efficient forthis step. The products are derivatives (9) of 3-substituted(4S)-4-hydroxycyclopent-2-en-1-ones, in which R² is an alkyl, alkenyl,alkynyl or otherwise functionalised alkyl substituent derived from theorganometallic reagent, and in which the functionality is compatibleboth with this step and with subsequent steps.

Stereospecific reduction of the 1-carbonyl function in these3-substituted enones (9) for example with a suitable metal hydride,gives derivatives (10) of 3-substituted (1R,4S)-cyclopent-2-en-1,4-diols in which the 1- and 4-substituents have cisrelative stereochemistry and in which the 4-hydroxyl function remainsprotected. Protection of the newly-formed 1-hydroxyl function of thealcohols (10) with a suitable group R³ which is stable to the ensuingreaction conditions but which can be selectively removed when necessary,yields derivatives (11) of 2-substituted (1S,4R)-cyclopent-2-en-1,4-diols in which both the 1- and 4-hydroxylsubstituents are now protected. [Note that IUPAC Nomenclature Rulesrequire a change of numbering in derivatives of type (11) compared tothose of type (10)].

Selective removal of the R¹ protecting group from the 1-hydroxylfunction of these diol derivatives (11) yields derivatives (12) of2-substituted (1S, 4R)-cyclopent-2-en-1,4-diols in which the 4-hydroxylfunction only is now protected. Oxidation of the 1-hydroxyl function inthese alcohols (12) gives derivatives (13) of 2-substituted(4R)-4-hydroxy-cyclopent-2-en-1-ones, in which the 4-hydroxyl functionis still protected.

2-substituted (4R)-4-hydroxycyclopent-2-en-1-one derivatives of type(13) have previously been converted into prostanoids via conjugateaddition reactions (C. J. Sih, J. B. Heather, R. Sood, P. Price, G.Peruzzotti, L. F. H. Lee and S. S. Lee, J. Am. Chem. Soc., 1975, 97,865; G. Stork and T. Takahashi, J. Am. Chem. Soc., 1977, 99, 1275).Alternatively, the R³ protecting group can be removed from the4-hydroxyl function of these derivatives (13) and replaced by analternative protecting group prior to conversion into prostanoids.

The substituent R² in the derivatives (9) of 3-substituted(4S)-4-hydroxycyclopent-2-en-1-ones may, as stated above, be an alkyl,alkenyl, alkynyl or otherwise functionalised alkyl substituent. Itsfunctionality is initially limited by the requirement for compatibilitywith the organometallic process by which it is introduced. Thissubstituent R² may if desired, however, be modified subsequent to itsintroduction. Such modification may be carried out either on the3-substituted enones (9) or at any appropriate later stage or stages inthe sequence from these 3-substituted enones (9) through the substitutedcyclopentenes (10), (11) and (12) to the 2-substituted(4R)-4-hydroxycyclopent-2-en-1-one derivatives of type (13). The carbonchain itself may be modified, or optional substituents in it may beadded, replaced, or modified. It will be understood that such reactionscarried out on the side-chain must be compatible with the structuralfeatures of the particular nucleus of type (9), (10), (11), (12) or (13)to which it is attached, and the resulting modified R² side-chain mustitself be compatible with any subsequent process carried out.

If the (1S, 4S)-enantiomer (5) of the racemic acid (3) is subjected to asimilar sequence of reactions to that described above, the derivatives(18) of 2-substituted (4S)-4-hydroxycyclopent-2-en-1-ones result, whichare enantiomeric to the 2-substituted (4R)-4-hydroxycyclopent-2-en-1-onederivatives of type (13). However, (4R)-derivatives of type (13) canalso be prepared from the (1S, 4S)-enantiomer (5) of the racemic acid(3) by carrying out an inversion of configuration. It will beappreciated that this inversion may be effected at any appropriate stageof the synthesis, and that only one such inversion is necessary eventhough some of the intermediates contain two chiral centres. Forexample, inversion of the configuration of the hydroxyl function in thederivatives (19) of the 3-substituted (1S, 4R)-cyclopent-2-en-1,4-diolsyields derivatives (20; R³ =H) of 3-substituted (1R,4R)-cyclopent-2-en-1,4-diols in which the ring oxygen functions are nowtrans- rather than cis-related. Biomolecular nucleophilic substitutionreactions are suitable for this inversion. Subsequent reaction stepssimilar to those carried out on the cis-derivatives (10) then lead, viadestruction of the non-inverted chiral centre, to the 2-substituted(4R)-4-hydroxycyclopent-2-en-1-one derivatives of type (13). (In thedetailed Examples which follow, this inversion of configuration isillustrated on racemic material, since the change in relativestereochemistry is sufficient to establish that inversion has occurred).

Furthermore, the nature of the processes described permits thepreparation of prostanoids which are isotopically labelled at specificsites. Such labelled compounds are of value in biological studies ofprostanoids and their metabolites, in which various techniques areemployed such as radioactive assay, radioimmunoassay, mass spectroscopyand coupled gas chromatography-mass spectroscopy. (See for example, B.Samuelsson, E. Granstrom, K. Green, M. Hamberg, and S. Hammarstrom, Ann.Rev. Biochem., 1975, 44, 669). Appropriate isotopic labels includedeuterium or tritium, and/or carbon-13 or carbon-14. These labelledatoms can be introduced at various stages of the processes described byemploying an appropriate isotopically labelled substrate and/or anisotopically labelled reagent.

For example, the 2-substituted (4R)-4-hydroxycyclopent-2-en-1-onederivatives (13) may be prepared labelled with ¹⁴ C in all carbon atomsof the cyclopentenone ring by using [U-¹⁴ C] phenol as a startingmaterial for the above process, or specifically labelled in the R² -sidechain by use of the corresponding labelled organometallic species in theconjugate addition-elimination reaction which converts the chloro-enones(8) into the 3-substituted enones (9). Alternatively, the 2-substituted(4R)-4-hydroxycyclopent-2-en-1-one derivatives (13) may be labelled withdeuterium or tritium at C-5 of the cyclopentenone ring by using isotopicproton sources (e.g. deuterium oxide, or tritiated alcohols) in thereduction of the trichloro-enone (6) to the chloro-enone (7), or at C-4of the ring by use of deuterated or tritiated metal hydrides for thereduction of the 3-substituted enones (9) to the alcohols (10). Labelledprostanoids may then be prepared from such labelled 2-substituted(4R)-4-hydroxycyclopent-2-en-1-one derivatives (13).

Specific details of the compounds of the present invention and thereactions involved in the processes of this invention are illustrated bythe following detailed examples. In these examples, all temperatures arein degrees Centigrade, and technical terms (e.g. chromatography, etc.,)have the usual meaning in the art. Crude reaction products can bepurified by the means described herein, or by other means known in theart.

EXAMPLE 1(1R,4R)-3,5,5-Trichloro-1,4-dihydroxycyclopent-2-ene-1-carboxylic acid(4).

To (±)-3,5,5-trichloro-1,4-dihydroxycyclopent-2-ene-1-carboxylic acid(3) (A. W. Burgstahler, T. B. Lewis, and M. O. Abdel-Rahman, J. Org.Chem., 1966, 31, 3516; C. J. Moye and S. Sternhell, Aust. J. Chem., 196619, 2017) (10 g, 40.4 mmol) in methanol (1 l) was added (-)-brucine(15.94 g, 40.4 mmol) in methanol (1 l). Crystallisation at roomtemperature gave two crops (8.50 and 2.33 g respectively) of relativelypure (-)-brucine salt of the acid (4), [α]_(D) ²⁵ -110° (c 0.24, CHCl₃).Recrystallisation from methanol gave the pure (-)-brucine salt of theacid (4) (9.64 g, 74%) as colourless plates, m.p. 143°-146°, [α]_(D) ²⁵-120° (c 0.247, CHCl₃) (Found: C, 54.1; H, 4.85; Cl, 16.4; N, 4.05. C₂₉H₃₁ Cl₃ N₂ O₈ requires C, 54.25; H, 4.85; Cl, 16.55; N, 4.35%).

0.5 M-Hydrochloric acid (60 ml) was added to a suspension of the(-)-brucine salt of the acid (4) (5.6 g, 8.72 mmol) in ether (50 ml),and the mixture shaken until the salt had dissolved. The aqueous phasewas separated, extracted with ether (6×25 ml), and the combined ethersolutions were washed successively with 0.1 M-hydrochloric acid (20 ml)and saturated aqueous sodium chloride (2×15 ml) before drying (MgSO₄).Evaporation of the ether under reduced pressure gave the (1R, 4R)-acid(4) (2.03 g, 94%) as colourless rhombs from ether-light petroleum (b.p.40°-60°), m.p. 188°-190°, [α]_(D) ²⁵ -207° (c 0.100, EtOH), [α]₂₃₂ ²⁵-15,060° (c 5.18×10⁻³, EtOH), [θ]₂₁₉ ²⁵ -75,490° (c. 5.18×10⁻³, EtOH)(Found: C, 29.35; H, 1.95; Cl, 42.9.C₆ H₅ Cl₃ O₄ requires C, 29.1; H,2.05; Cl, 43.0%).

EXAMPLE 2 (4R)-3,5,5-Trichloro-4-hydroxycyclopent-2-en-1-one (6)

The (1R,4R)-acid (4) (200 mg, 0.8 mmol) was added portionwise over 10min to lead tetraacetate (500 mg, 1.13 mmol) in acetic acid (5 ml)containing water (0.05 ml) at 80°. After a further 5 min, water (25 ml)was added and the cooled mixture extracted with ether (3×25 ml). Thecombined ether solutions were extracted with 5% aqueous sodiumbicarbonate until the washings were alkaline (pH 7.5-8), then washedwith water (10 ml), dried (MgSO₄), and evaporated under reducedpressure. Short path distillation (bath temp. 60°/0.1 mmHg) gave the(4R)-enone (6) (160 mg, 98%) as a colourless oil, [α]₃₅₇ ²⁵ +1547° (c5.66×10⁻², EtOH), [α]₂₅₂ ²⁵ -11,280° (c 2.26×10⁻³, EtOH), [θ]₃₃₃ ²⁵+8407° (c 5.66×10⁻², EtOH), [θ]₂₄₀ ²⁵ -45,025° (c 2.26×10⁻³, EtOH)(Found: C, 29.8; H, 1.65; Cl, 51.3; C₅ H₃ Cl₃ O₂ requires C, 29.8; H,1.5; Cl, 52.8%).

EXAMPLE 3 (4S)-3-Chloro-4-hydroxycyclopent-2-en-1-one (7)

To the (4R)-trichloro-enone (6) (325 mg, 1.61 mmol) in acetone (8 ml) at0° and under carbon dioxide was added an aqueous solution (15 ml) ofchromium (II) chloride (J. R. Hanson, Synthesis, 1974, 1; G. Rosenkranz,O. Mancera, J. Gatica, and C. Djerassi, J. Am. Chem. Soc. 1950, 72,4077) at 0°. After 15 min the solution was extracted with ether (3×30ml), and the combined extracts were evaporated under reduced pressure.The residue was dissolved in ether (30 ml), dried (MgSO₄) and evaporatedto yield the crude (4S)-enone (7) (247 mg) as a thermally unstable oil.This crude product showed similar behaviour on thin layer chromatography(silica gel, methylene dichloride-methanol, 10:1) to the purified, fullycharacterised racemic material, and was used without furtherpurification.

EXAMPLE 4 (4S)-3-Chloro-4-(dimethyl-t-butylsilyloxy)cyclopent-2-en-1-one(8; R¹ =Me₂ Bu^(t) Si)

Chlorodimethyl-t-butylsilane (485 mg, 3.22 mmol) was added over 5 min tothe crude (4S)-enone (7) (247 mg) in hexamethylphosphoric triamide (2ml) at 0°. After stirring at 4° for 20 h the solution was diluted withwater (10 ml) and extracted with ether (3×10 ml). The combined etherextracts were washed with water (3×10 ml), dried (MgSO₄) and evaporatedto give a pale yellow oil (456 mg) which was chromatographed on a columnof silica gel (25 g) with methylene dichloride-methanol (50:1) aseluant. The (4S)-enone (8; R¹ =Me₂ Bu^(t) Si) [243 mg, 61% from the3,5,5-trichloro-4-hydroxycyclopent-2-en-1-one (6)] was obtained as acolourless oil, [α]₃₅₂ ²⁵ +1050° (c. 9.14×10⁻², hexane), [α]₂₃₄ ²⁵-16,140° (c 1.83×10⁻³, hexane), [θ]₃₃₃ ²⁵ +6700° (c 9.14×10⁻², hexane),[θ]₂₂₂ ²⁵ -80,330° (c 1.83×10⁻³, hexane). (Found: C, 53.65; H, 7.95; Cl,14.6. C₁₁ H₁₉ ClO₂ Si requires C, 53.55; H, 7.75; Cl, 14.35%)

EXAMPLE 5(4S)-4-(Dimethyl-t-butylsilyloxy)-3-[7-(dimethyl-t-butylsilyloxy)heptyl]-cyclopent-2-en-1-one(9; R¹ =Me₂ Bu^(t) Si, R² =(CH₂)₇ OSiMe₂ Bu^(t))

A suspension of cuprous iodide (64 mg, 0.326 mmol) in tetrahydrofuran (2ml) containing the (4S)-enone (8; R¹ =Me₂ Bu^(t) Si) (80 mg, 0.326 mmol)was stirred vigorously at -10° under argon. Dropwise addition of7-(dimethyl-t-butylsilyloxy)heptyl magnesium bromide in tetrahydrofuran(0.52 M, 1.0 ml, 0.620 mmol) produced a green solution which was stirredat -10° for 10 min. The reaction was rapidly quenched with saturatedaqueous ammonium chloride (5 ml), and after the addition of ether (5 ml)the mixture was stirred at room temperature for 1 h before dilution withwater (10 ml) and extraction with ether (5×10 ml). The combined extractswere washed with brine (2×5 ml), dried (MgSO₄) and evaporated.Purification by preparative layer chromatography on silica gel inmethylene dichloride-methanol (50:1) gave the (4S)-enone (9; R¹ =Me₂Bu^(t) Si, R² =(CH.sub. 2)₇ OSiMe₂ Bu^(t)) (127 mg, 89%) as a colourlessoil, [α]₃₆₂ ²⁵ +781°, [α]₃₄₆ ²⁵ +781° (c 1.665×10⁻², hexane), [α]₂₂₈ ²⁵-11,110° (c 1.665×10⁻³, hexane), [θ]₃₂₆ ²⁵ +8538° (c 1.665×10⁻²,hexane), [θ]₂₁₇ ²⁵ -95,970° (c 1.665×10⁻³, hexane) (Found: C, 65.55; H,11.05. C₂₄ H₄₈ O₃ Si₂ requires C, 65.4; H, 11.0%).

EXAMPLE 6(1R,4S)-4-(Dimethyl-t-butylsilyloxy)-3-[7-(dimethyl-t-butylsilyloxy)heptyl]-cyclopent-2-en-1-ol(10; R¹ =Me₂ Bu^(t) Si, R² =(CH₂)₇ OSiMe₂ Bu^(t))

Lithium tri-s-butylborohydride in tetrahydrofuran (1 M, 1.6 ml, 1.6mmol) was added dropwise with vigorous stirring to the (4S)-enone (9; R¹=Me₂ Bu^(t) Si, R² =(CH₂)₇ OSiMe₂ Bu^(t)) (350 mg, 0.79 mmol) intetrahydrofuran (3 ml) at -78°. After 3 h at this temperature water (1ml) was added and the mixture allowed to warm to room temperature.Dilution with water (10 ml) and extraction with ether (4×10 ml) gave,after drying (MgSO₄) and evaporation of the extracts, a pale yellow oil(690 mg). Preparative layer chromatography on silica gel in methylenedichloride-methanol (20:1) yielded the (1R,4S)-alcohol (10; R¹ =Me₂Bu^(t) Si, R² =(CH₂)₇ OSiMe₂ Bu^(t)) (287 mg, 82%) as a colourless oil.(Found: C 65.4; H, 10.95. C₂₄ H₅₀ O₃ Si₂ requires C, 65.1; H, 11.4%).

EXAMPLE 7(1S,4R)-1-(Dimethyl-t-butylsilyloxy)-2-[7-(dimethyl-t-butylsilyloxy)heptyl]-4-(tetrahydropyran-2-yloxy)cyclopent-2-ene(11; R¹ =Me₂ Bu^(t) Si, R² =(CH₂)₇ OSiMe₂ Bu^(t), R³ =Thp).

Dihydropyran (45.9 mg, 0.546 mmol) was added dropwise to the(1R,4S)-alcohol (10; R¹ =Me₂ Bu^(t) Si, R² =(CH₂)₇ OSiMe₂ Bu^(t)) (220mg, 0.497 mmol) in methylene dichloride (4 ml) containingp-toluenesulphonic acid (0.01 M) at 0°. After 3 hr. the solution wasdiluted with ether (15 ml), washed successively with 5% aqueous sodiumbicarbonate (5 ml) and water (2×5 ml), and then dried (MgSO₄). Removalof the solvet under reduced pressure and chromatography of the residueon a column of silica gel (30 g) in methylene dichloride-methanol (50:1)gave the (1S,4R)-diol derivative (11; R¹ =Me₂ Bu^(t) Si, R² =(CH₂)₇OSiMe₂ Bu^(t), R³ =Thp) (197 mg, 75%) as a colourless oil. (Found: C,66.4; H, 11.1. C₂₉ H₅₈ O₄ Si₂ requires C, 66.1; H, 11.1%).

EXAMPLE 8(1S,4R)-2-(7-Hydroxyheptyl)-4-(tetrahydropyran-2-yloxy)cyclopent-2-en-1-ol(12; R² =(CH₂)₇ OH, R³ =Thp)

To the (1S,4R)-diol derivative (11: R¹ =Me₂ Bu^(t) Si, R² =(CH₂)₇ OSiMe₂Bu^(t), R³ =Thp) (174 mg, 0.33 mmol) in tetrahydrofuran (3 ml) at 0° wasadded slowly tetrabutylammonium fluoride in tetrahydrofuran (0.4 M, 4ml). After 4 h at 0° the solution was diluted with water (5 ml) andextracted three times with ether (20 ml, 2×10 ml). The combined extractswere washed with saturated brine (2×10 ml), dried (MgSO₄), andevaporated. Chromatography of the residual oil on a column of silica gel(7 g) in methylene dichloridemethanol (10:1) gave the (1S,4R)-diol (12;R² =(CH₂)₇ OH, R³ =Thp) (92 mg, 93%) as a colourless oil (Found: C,68.6; H, 10.0. C₁₇ H₃₀ O₄ requires C, 68.4; H, 10.15%).

EXAMPLE 9(4R)-2-(6-Carboxyhexyl)-4-(tetrahydropyran-2-yloxy)cyclopent-2-en-1-one*(13; R² =(CH₂)₆ CO₂ H, R³ =Thp)

Jones reagent (K. Bowden, I. M. Heilbron, E. R. H. Jones, and B. C. L.Weedon, J. Chem. Soc., 1946, 39) was added over 2.5 h to the(1S,4R)-diol (12; R² =(CH₂)₇ OH, R³ =Thp) (74 mg, 0.248 mmol) in acetone(6 ml) at -20° so that an excess of oxidant was maintained. After afurther 30 min isopropanol was added to destroy excess of oxidant. Thesolution was diluted with water (10 ml), extracted with ether (5×10 ml),and the combined extracts were washed with saturated brine (3×5 ml),dried (MgSO₄), and evaporated under reduced pressure. The (4R)-acid (13;R² =(CH₂)₆ CO₂ H, R³ =Thp) (75 mg) was obtained as a chromatographicallypure oil (Found: M⁺, 310.1780. C₁₇ H₂₆ O₅ requires M, 310.1780).

EXAMPLE 10(4R)-2-(6-Methoxycarbonylhexyl)-4-(tetrahydropyran-2-yloxy)cyclopent-2-en-1-one**(13; R² =(CH₂)₆ CO₂ Me, R³ =Thp)

An excess of ethereal diazomethane was added to the chromatographicallypure (4R)-acid (13; R² =(CH₂)₆ CO₂ H, R³ =Thp) (75mg) in ether (10 ml).After 30 min the excess of reagent was destroyed by dropwise addition ofacetic acid, and the resulting ethereal solution was washed successivelywith 5% aqueous sodium bicarbonate (5 ml) and water (2×5 ml) beforedrying (MgSO₄). Removal of the ether under reduced pressure andpreparative layer chromatography of the residual oil on silica gel inmethylene dichloride-methanol (20:1) afforded the (4R)-ester (13; R²=(CH₂)₆ CO₂ Me, R³ =Thp) [67 mg, 83% from the (1S,4R)-diol (12; R²=(CH₂)₇ OH, R³ =Thp)] as a colourless oil, [α]₃₄₁ ²⁵ -1482° (c4.47×10⁻², MeOH), [α]₂₃₈ ²⁵ +10,510° (c 4.47×10⁻³, MeOH), [θ]₃₂₃ ²⁵-11,305° (c 4.47×10⁻², MeOH), [θ]₂₂₆ ²⁵ +63,785° (c 4.47×10⁻³, MeOH)(Found: C, 66.35; H, 8.6. C₁₈ H₂₈ O₅ requires C, 66,65; H,8.7%).

EXAMPLE 11(4R)-4-Hydroxy-2-(6-methoxycarbonylhexyl)cyclopent-2-en-1-one* (13; R²=(CH₂)₆ CO₂ Me, R³ =H)

The (4R)-ester (13; R² =(CH₂)₆ CO₂ Me, R³ =Thp) (40 mg, 0.123 mmol) inacetic acid-tetrahydrofuran-water (3:1:1, 2 ml) was maintained at roomtemperature for 24 h. Solvent was removed under reduced pressure, andthe residue, dissolved in ethyl acetate (10 ml), was washed successivelywith 5% aqueous sodium bicarbonate (5 ml) and saturated brine (2×5 ml).After drying (MgSO₄), the solvent was removed under reduced pressure andthe residual oil crystallised from ether-pentane at -10° to yield the(4R)-ester (13; R² =(CH₂)₆ CO₂ Me, R³ =H) (21 mg) as rhombs, m.p.56°-59°. Preparative layer chromatography of the mother liquors onsilica gel in methylene dichloridemethanol (10:1), followed bycrystallisation from ether-pentane, gave further (4R)-ester (13; R²=(CH₂)₆ CO₂ Me, R³ =H) (5 mg; total yield 26 mg, 88%), [α]₃₄₅ ²⁵ -1560°(c 4.14×10⁻², MeOH), [α]₂₃₇ ²⁵ +14,240° (c 4.14×10⁻³, MeOH), [θ]₃₂₀ ²⁵-9858° (c 4.14×10⁻² , MeOH), [θ]₂₂₄ ²⁵ +64730° (c 4.14×10⁻³, MeOH), withspectroscopic properties in agreement with literature data (Found: C,65.3; H, 8.6. C₁₃ H₂₀ O₄ requires C, 65.0; H, 8.4%).

EXAMPLE 12(1S,4S)-3,5,5-Trichloro-1,4-dihydroxycyclopent-2-ene-1-carboxylic acid(5).

After crystallisation of the (-)-brucine salt of the acid (4) in Example1, gradual reduction in the volume of methanol produced several crops ofdextrorotatory (-)-brucine salt (total 13.04 g). Severalrecrystallisations from ethanol gave the pure (-)-brucine salt of acid(5) (9.58 g, 74%) as colourless needles, m.p. 149°-152° (dec.), [α]_(D)²⁵ +93° (c. 0.265, CHCl₃) (Found: C, 54.35; H, 5.25; Cl, 16.35; N, 4.1.C₂₉ H₃₁ Cl₃ N₂ O₈ requires C, 54.25; H, 4.85; Cl, 16.55; N, 4.35%).

Acidification of the salt (4.45 g) gave the (1S, 4S)-acid(5) (1.70 g,99%) as colourless rhombs from ether-light petroleum (b.p. 40°-60°) m.p.188°-189°, [α]_(D) ²⁵ +207° (c 0.110, EtOH), [α]₂₃₂ ²⁵ +15,420° (c4.93×10⁻³, EtOH), [θ]₂₁₉ ²⁵ +76,310 (c 4.93×10⁻³, EtOH) (Found: C, 29.5;H, 2.15; Cl, 42.95 C₆ H₅ Cl₃ O₄ requires C, 29.1; H, 2.05; Cl, 43.0%).

EXAMPLE 13 (4S)-3,5,5-Trichloro-4-hydroxycyclopent-2-en-1-one (15)

Obtained by a process analogous to Example 2 from the (1S,4S)-acid as acolourless oil after short path distillation (bath temp. 50°/0.05 mmHg), [α]₃₅₇ ²⁵ -1610° (c 5.05×10⁻², EtOH), [α]₂₅₂ ²⁵ +14,600° (c2.02×10⁻³, EtOH), [θ]₃₃₃ ²⁵ -8940 (c 5.05×10⁻², EtOH), [θ]₂₄₀ ²⁵ +46,600(c 2.02×10⁻³, EtOH) (Found: C, 29.7; H, 1.8; Cl, 51.7. C₅ H₃ Cl₃ O₂requires C, 29.8; H, 1.5; Cl, 52.8%).

EXAMPLE 14(4R)-3-chloro-4-(dimethyl-t-butylsilyloxy)-cyclopent-2-en-1-one (17; R¹=Me₂ Bu^(t) Si).

Obtained by a process analogous to Example 3 from the(4S)-trichloro-enone (15) as a colourless oil, [α]₃₅₂ ²⁵ -1050° (c3.15×10⁻², hexane), [α]₂₃₄ ²⁵ +17,290° (c 1.58×10⁻³, hexane), [θ]₃₃₃ ²⁵-6770 (c 3.15×10⁻², hexane) [θ]₂₂₅ ²⁵ +83,780 (c 1.58×10⁻³ hexane)(Found: C, 53.8; H, 7.8; Cl, 14.5. C₁₁ H₁₉ ClO₂ Si requires C, 53.55; H,7.75; Cl, 14.35%).

EXAMPLE 15(4S)-4-(Dimethyl-t-butylsilyloxy)-3-[7-(tetrahydropyran-2-yloxy)heptyl]-cyclopent-2-en-1-one (9; R¹ =Me₂ Bu^(t) Si, R² =(CH₂)₇ OThp)

A suspension of cuprous iodide (76 mg, 0.4 mmol) in tetrahydrofuran (2ml) containing the (4S)-enone (8; R¹ =Me₂ Bu^(t) Si) (100 mg, 0.4 mmol)was stirred vigorously at -10° under argon. Dropwise addition of7-(tetrahydropyran-2-xyloxy)heptyl magnesium bromide in tetrahydrofuran(0.47 M, 1.62 ml, 0.76 mmol) produced a green solution which was stirredat -10° for 10 min. The reaction was rapidly quenched with saturatedaqueous ammonium chloride (5 ml), and after the addition of ether (5 ml)the mixture was stirred at room temperature for 1 hr., before dilutionwith water (10 ml) and extraction with ether (5×10 ml). The combinedextracts were washed with brine (2×5 ml) dried (MgSo₄) and evaporated.Purification by preparative layer chromatography on silica gel inmethylene dichloride-methanol (50:1) gave the (4S)-enone (9;R¹ =Me₂Bu^(t) Si, R² =(CH₂)₇ OThp) (135 mg, 83%) as a colourless oil, [α]₃₆₂ ²⁵+795°; [α]₃₄₅ ²⁵ +795° (c 1.825×10⁻², hexane), [α]₂₂₈ ²⁵ -11,200° (c.1.825×10⁻³, hexane), [θ]₃₂₄ ²⁵ +8670 (c 1.825×10⁻², hexane), [θ]₂₁₇ ²⁵-96,150 (c 1.825×10⁻³, hexane) (Found: C, 67.5; H, 10.25. C₂₃ H₄₂ SiO₄requires C, 67.25; H, 10.3%).

EXAMPLE 16 (1R,4S)-4-(Dimethyl-t-butylsilyloxy)-3-[7-(tetrahydropyran-2-yloxy)heptyl]-cyclopent-2-en-1-ol (10; R¹ =Me₂ Bu^(t) Si, R² =(CH₂)₇ OThp)

Lithium tri-s-butylborohydride in tetrahydrofuran (1 M, 0.508 ml, 0.508mmol) was added dropwise with vigorous stirring to the (4S)-enone (9; R¹=Me₂ Bu^(t) Si; R² =(CH₂)₇ Othp) (180 mg, 0.44 mmol) in tetrahydrofuran(3 ml) at -78°. After 1 hr. at this temperature, water (1 ml) was addedand the mixture allowed to warm to room temperature. Dilution with water(10 ml) and extraction with ether (4×10 ml) gave, after drying (MgSo₄)and evaporation of the extracts a pale yellow oil (264 mg). Preparativelayer chromatography on silica gel in methylene dichloride-methanol(50:1) yielded the (1R, 4S)-alcohol (10; R¹ =Me₂ Bu^(t) Si, R² =(CH₂)₇OThp) (145 mg, 80%) as a colourless oil (Found: C, 66.65; H. 10.4. C₂₃H₄₄ O₄ Si requires C, 66.95; H, 10.75 %).

EXAMPLE 17(1S,4R)-1-(Dimethyl-t-butylsilyloxy)-2-[7-(tetrahydropuran-2-xyloxy)heptyl]-4-(tetrahydropyran-2-yloxy)cyclopent-2-ene(11; R¹ =Me₂ Bu^(t) Si, R² =(CH₂)₇ OThp, R³ =Thp)

Dihydropyran (21.3 mg, 0.25 mmol) was added dropwise to the (1R,4S)-alcohol (10; R¹ =Me₂ Bu^(t) Si, R² =(CH₂)₇ OThp (60 mg, 0.145 mmol)in methylene dichloride (1.5 ml) containing pyridinium p-toluenesulphonate (4 mg, 0.02 mmol). After 3 h, at room temperature thesolution was diluted with ether (10 ml) washed with half-saturated brine(2×10 ml), dried (MgSO₄) and evaporated. Preparative layerchromatography of the residue (81 mg) on silica gel in methylenedichloride methanol (50:1) gave the (1S, 4R)-diol derivative (11; R¹=Me₂ Bu^(t) Si, R² =(CH₂)HD 7OThp, R³ =Thp (66 mg, 92%) as a colourlessoil (Found: C, 68.3; H, 10.8. C₂₈ H₅₂ O₅ Si requires C, 67.7; H, 10.55%.

EXAMPLE 18(1S,4R)-2-[7-(Tetrahydropyran-2-yloxy)heptyl]-4-(tetrahydropyran-2-yloxy)cyclopent-2-en-1-ol)(12; R² =(CH₂)₇ OThp, R³ =Thp)

To the (1S, 4R)-diol derivative (11; R¹ =Me₂ Bu^(t) Si, R² =(CH₂)₇ OThp,R³ =Thp) (174 mg, 0.35 mmol) in tetrahydrofuran (3 ml) at 0° was addeddropwise tetrabutylammonium fluoride in tetrahydrofuran (0.4 M, 1.75ml). After 5.5 h at 0° the solution was diluted with water (5 ml) andextracted with ether (3×10 ml). The combined extracts were washed withsaturated brine (2×5 ml), dried (MgSO₄), and evaporated. Chromatography(p.l.c.) of the residual oil (240 mg) on silica gel in methylenedichloride-methanol (50:1) gave the (1S, 4R)-cyclopentenol (12; R²=(CH₂)₇ OThp, R³ =Thp) (122 mg, 91%) as a colourless oil (Found: C.69.30 H, 10.2, C₂₂ H₃₈ O₅ requires C, 69.05; H, 10.0%).

EXAMPLE 19 (4R)-2-[7-(tetrahydropyran-2-yloxy)heptyl]-4-(tetrahydropyran-2-yloxy)cyclopent-2-en-1-one(13; R² =(CH₂)₇ OThp R³ =Thp)

Pyridinium chlorochromate (110 mg, 0.51 mmol) was added in one portionto a suspension of anhydrous sodium acetate (8 mg, 0.1 mmol) inmethylene dichloride (2 ml) containing the (1S,4R)-cyclopentenol (12; R²=(CH₂)₇ OThp, R³ =Thp) (122 mg, 0.32 mmol).

After stirring at room temperature for 2 h the mixture was diluted withether (10 ml) and the reduced reagent was removed by filtration througha pad of "Florisil". Evaporation of the solvent under reduced pressureand chromatographic purification of the residual oil (133 mg) on silicagel in methylene-dichloride-methanol (50:1) gave the (4R)-cyclopentenone(13; R² =(CH₂)₇ Othp, R³ =Thp) (117 mg, 96%) as a colourless oil, [α]₃₄₂²⁵ -1140° (C 2.625×10⁻², MeOH), [α]₂₃₈ ²⁵ +10,285° (c 0.525×10⁻², MeOH),[θ]₃₁₈ ²⁵ -10,510 (c 2.625×10⁻², MeOH), [θ]₂₂₇ ²⁵ +73,930 (c 0.525×10⁻²,MeOH) (Found: C, 70.05; H, 9.55. C₂₂ H₃₆ O₅ requires C, 69.45; H,9.55%).

EXAMPLE 20 (4R)-2-(7-Hydroxyheptyl)- 4-hydroxycyclopent-2-en-1-one (13;R² =(CH₂)₇ OH, R³ =H)

The (4R)-bis-tetrahydropyran-2-yl ether (13; R² =(CH₂)₇ OThp, R³ =Thp)(100 mg, 0.263 mmol) in aqueous acetic acid (80%, 1 ml) containing atrace of tetrahydrofuran was maintained at room temperature for 48 h.Solvent was removed under reduced pressure and the residue was purifiedby preparative layer chromatography on silica gel in methylenedichloride-methanol (20:1) to yield the (4R)-cyclopentenone (13; R²=(CH₂)₇ OH, R³ =H) (54 mg, 98%) as colourless needles fromchloroform-light petroleum (b.p. 60°-80°), m.p. 63°-65° [α]₃₄₅ ²⁵ -1845°(c 3.58×10⁻², MeoH), [α]₂₃₈ ²⁵ +17,320° (c. 3.58×10⁻³, MeOH), [θ]₃₁₆ ²⁵-8660 (c 3.58×10⁻², MeOH) [θ]₂₂₂ ²⁵ +49,810 (c, 3.58×10⁻³, MeOH) (Found:C, 67.95; H, 9.4. C₁₂ H₂₀ O₃ requires C, 67.9; H 9.5%.)

EXAMPLE 21(4RS)-4(Dimethyl-t-butylsilyloxy)-3-(7-hydroxyheptyl)cyclopent-2-en-1-one((±)-9; R¹ =Me₂ Bu^(t) Si, R² =(CH₂)₇ OH)

(4RS)-4-(Dimethyl-t-butylsilyloxy)-3-[7-(dimethyl-t-butylsilyloxy)heptyl]-cyclopent-2-en-1-one((±)-9; R¹ =Me₂ Bu^(t) Si, R² =(CH₂)₇ OSiMe₂ Bu^(t)) (69 mg, 0.156 mmol)in acetic acid-tetrahydrofuran-water (3:1:1, 0.5 ml) was maintained atroom temperature for 17 h. Removal of the solvent under reduced pressureand preparative layer chromatography of the residual oil on silica gelin methylene dichloride-methanol (20:1) afforded the primary alcohol((±)-9; R¹ =Me₂ Bu^(t) Si, R² =(CH₂)₇ OH)(46 mg, 90%) as a colourlessoil (Found: C, 66.6; H, 10.4. C₁₈ H₃₄ O₃ Si requires C, 66.2; H, 10.5%).

EXAMPLE 22(4RS)-3-(6-Carboxyhexyl)-4-(dimethyl-t-butylsilyloxy)cyclopent-2-en-1-one((±)--9; R¹ =Me₂ Bu^(t) Si, R² =(CH₂)₆ CO₂ H)

Jones reagent was added over 3 h to the primary alcohol ((±)-9; R¹ =Me₂Bu^(t) Si, R² =(CH₂)₇ OH (175 mg, 0.536 mmol) in acetone (10 ml) at -10°so that an excess of oxidant was maintained. After this time,isopropanol was added to destroy excess of oxidant. The solution wasdiluted with water (20 ml), extracted with ether (5×15 ml), and thecombined extracts were washed with saturated brine (2×5 ml), dried(MgSO₄) and evaporated under reduced pressure. The oily carboxylic acid((±)-9; R¹ =Me₂ Bu^(t) Si, R² =(CH₂)₆ CO₂ H) (165 mg, 90%) obtained washomogeneous by thin layer chromatography and was employed withoutfurther purification.

EXAMPLE 23(4RS)-4-(Dimethyl-t-butylsilyloxy)-3-(6-ethoxycarbonylhexyl)cyclopent-2-en-1-one((±)-9; R¹ =Me₂ Bu^(t) Si, R² =(CH₂)₆ CO₂ Et)

A solution of 1,5-diazabicyclo[5.4.0]undec-5-ene(DBU, 73.6 mg 0.484mmol) in benzene (0.5 ml) was added with stirring to thechromatographyically pure acid ((±)-9; R¹ =Me₂ Bu^(t) Si, R² =(CH₂)₆ CO₂H)(165 mg, 0.484 mmol) and ethyl iodide (75.5 mg, 0.484 mmol) in benzene(1.5 ml) at room temperature. After 18 h the mixture was filtered andthe filtrate was evaporated under reduced pressure to yield a paleyellow oil. Chromatographic purification on silica gel in methylenedichloride-methanol (20:1) gave the ester ((±)-9; R¹ =Me₂ Bu^(t) Si, R²=(CH₂)₆ CO₂ Et) (147 mg, 96% based on acid consumed) as a colourless oil(Found: C, 65.35; H, 9.75. C₂₀ H₃₆ O₄ Si requires C, 65.15; H, 9.85%).

EXAMPLE 24 (1R*, 4S*)-4-(Dimethyl-t-butylsilyloxy)-3-(6-ethoxycarbonyl-hexyl)cyclopent-2-en-1-ol ((±)-10; R¹ =Me₂ Bu^(t) Si;R² =(CH₂)₆ CO₂ Et)

Lithium tri-s-butylborohydride in tetrahydrofuran (1M, 0.150 ml, 0.150mmol) was added dropwise with vigorous stirring to the enone ((±)-9; R¹=Me₂ Bu^(t) Si, R² =(CH₂)₆ CO₂ Et)(50 mg, 0.136 mmol) in tetrahydrofuran(1 ml) at -78°. After 0.5 h at this temperature water (0.5 ml) was addedand the mixture allowed to warm to room temperature. Dilution with water(5 ml) and extraction with ether (4×5 ml) gave, after drying (MgSO₄) andevaporation of the combined extracts, a pale yellow oil (60 mg).Preparative layer chromatography on silica gel in methanedichloride-methanol (20:1) yielded the (1R*, 4S*)-alcohol ((±)-10; R¹=Me₂ Bu^(t) Si, R² =(CH₂)₆ CO₂ Et) (47 mg, 93%) as a colourless oil(Found: C, 65.1; H, 10.2. C₂₀ H₃₈ O₄ Si requires C, 64.8; H, 10.35%).

EXAMPLE 25 (1S*,4R*)-1-(Dimethyl-t-butylsilyloxy)-2-(6-ethoxycarbonyl-hexyl)-4-(tetrahydropyran-2-yloxy)cyclopent-2-ene((±)-11; R¹ =Me₂ Bu^(t) Si; R² =(CH₂)₆ CO₂ ET.sub.μ, R³ =Thp)

Dihydropyran (16.8 mg, 0.2 mmol) was added dropwise to the (1R*,4S*)-alcohol ((±)-10; R¹ =Me₂ Bu^(t) Si; R² =(CH₂)₆ CO₂ Et) (50 mg,0.135 mmol) in methylene dichloride (1 ml) containing pyridiniump-toluenesulphonate (3 mg, 0.015 mmol). After 4 h at room temperaturethe solution was diluted with ether (10 ml), washed with half-saturatedbrine (10 ml), dried (MgSO₄) and evaporated. Preparative layerchromatography of the residue (74 mg) on silica gel in methylenedichloride-methanol (50:1) gave the (1S*, 4R*)-diol derivative ((±)-11;R¹ =Me₂ Bu^(t) Si, R² =(CH₂)₆ CO₂ Et, R³ =Thp) (61 mg, 100%) as acolourless oil (Found: C, 66.15; H, 10.15. C₂₅ H₄₆ O₅ Si requires C,66.05; H, 10.2%.

EXAMPLE 26 (1 S*,4R*)-2-(6-Ethoxycarbonylhexyl)-4-(tetrahydropyranyloxy)cyclopent-2-en-1-ol((±)-12; R² =(CH₂)₆ CO₂ Et. R³ =Thp)

To the (1S*, 4R*)-diol derivative ((±)-11; R¹ =Me₂ Bu^(t) Si, R² =(CH₂)₆CO₂ Et, R³ =Thp) (55 mg, 0.12 mmol) in tetrahydrofuran (1 ml) at 0° wasadded dropwise tetrabutylammonium fluoride in tetrahydrofuran (0.4 M,0.6 ml). After 5.5 h at 0° the solution was diluted with water (5 ml)and extracted with ether (3×10 ml). The combined extracts were washedwith saturated brine (2×5 ml), dried (MgSO₄) and evaporated.Chromatographic purification of the residue (55 mg) on silica gel inmethylene dichloride-methanol (20:1) gave the (1S*, 4R*)-cyclopentenol((±)-12; R² =(CH₂)₆ CO₂ Et, R³ =Thp) (37 mg, 90%) as a colourless oil(Found: C, 67.35; H, 9.35, C₁₉ H₃₂ O₅ requires C, 67.05; H, 9.5%).

EXAMPLE 27 (4RS)-2-(6-Ethoxycarbonylhexyl)-4-(tetrahydropyran-2-yloxy)cyclopent-2-en-1-one ((±)-13; R² =(CH₂)₆ CO₂ Et, R³ =Thp)

Pyridinium chlorochromate (24 mg, 0.11 mmol) was added to a suspensionof anhydrous sodium acetate (2 mg, 0.025 mmol) in methylene dichloride(1 ml) containing the (1S*, 4R*)-alcohol ((±)-12; R² =(CH₂)₆ CO₂ Et, R³=Thp)(23 mg, 0.067 mmol).

After stirring at room temperature for 2 h the mixture was diluted withether (3 ml) and filtered through a pad of "Florisil". Evaporation ofthe filtrate under reduced pressure and chromatographic purification ofthe residual oil on silica gel in methylene dichloride-methanol (100:5)gave the ester ((±)-13; R² =(CHO₂)₆ C₂ Et, R³ =Thp)(21 mg, 93%) as acolourless oil (Found: C, 67.3; H, 8.8. C₁₉ H₃₀ O₅ requires C, 67.45; H,8.95%).

EXAMPLE 28 (4RS)-2-(6-Ethoxycarbonylhexyl)-4-hydroxycyclopent-2-en-1-one((±)-13; R² =(CH₂)₆ CO₂ Et, R³ =H)

The ester ((±)-13, R² =(CH₂)₆ CO₂ Et, R³ =Thp) (70 mg, 0.21 mmol) inacetic acid-tetrahydrofuran-water (3:1:1:, 2 ml) was maintained at roomtemperature for 24 h. Solvent was removed under reduced pressure and theresidue was purified by preparative layer chromatography on silica gelin methylene dichloride-methanol (10:1) to yield the hydroxy-enone((±)-13; R² =(CH₂)₆ CO₂ Et, R³ =H) (53 mg, 99%) as a colourless oil(Found: C, 66.1; H, 8.7. C₁₄ H₂₂ O₄ requires C, 66.1; L H, 8.7%).

EXAMPLE 29(4RS)-3-butyl-4-(dimethyl-t-butylsilyloxy)cyclopent-2-en-1-one ((±)-9;R¹ =Me₂ Bu^(t) Si, R² =Bu)

(a) From Chloro-enone ((±)-8; R¹ =Me₂ Bu^(t) Si) and Lithiumn-Butyl(phenylthio) copper (I). n-Butyllithium in hexane (1.6 M, 0.32ml, 0.51 mmol) was added dropwise to a vigorously stirred suspension ofphenylthiocopper (I) (88 mg, 0.51 mmol) in tetrahydrofuran (5 ml) at-20° under argon. After 10 min at this temperature the pale yellowsolution was cooled to -78° and the chloro-enone ((±)-8; R¹ =Me₂ Bu^(t)Si) (85 mg, 0.34 mmol) in tetrahydrofuran (1 ml) was added dropwise. Themixture was allowed to warm to -20° over 1 h and after a further 1.5 hat this temperature the mixture was poured rapidly into saturatedaqueous ammonium chloride solution (10 ml) and covered by a layer ofether (20 ml). After stirring overnight the layers were separated andthe blue aqueous phase was extracted with ether (3×10 ml). The etherextracts were combined, washed successively with ammonium chloridesolution (10 ml) and saturated brine (2×10 ml), and then dried (MgSO₄).Removal of the solvent under reduced pressure and chromatography of theresidue on silica gel in methylene dichloride-methanol (50:1) gave theenone ((±)-9; R¹ =Me₂ Bu^(t) Si, R² =Bu) (67 mg, 74%) as a colourlessliquid (Found: C, 67.25; H, 10.3. C₁₅ H₂₈ O₂ Si requires C, 67.1; H,10.5%).

(b) From Chloro-enone ((±)-8; R¹ =Me₂ Bu^(t) Si) and ButylmagnesiumBromide

A suspension of cuprous iodide (68.5 mg, 0.36 mmol) in tetrahydrofuran(2 ml) containing the chloroenone ((±)-8; R¹ =Me₂ Bu^(t) Si) (88 mg,0.36 mmol) was stirred vigorously at 0° under argon. Dropwise additionof n-butyl magnesium bromide in tetrahydrofuran (0.72 M, 1 ml, 0.72mmol) produced a yellow-green solution which changed to deep-green over1 h at 0°. After this time the reaction was rapidly quenched withsaturated aqueous ammonium chloride (5 ml), and after the addition ofether (5 ml) the mixture was stirred at room temperature for 1 h beforedilution with water (10 ml) and extraction with ether (5×10 ml). Thecombined extracts were washed with brine (2×5 ml), dried (MgSO₄), andevaporated. The residual oil (126 mg) was purified as in (a) to give theenone ((±)-9; R¹ =Me₂ Bu^(t) Si, R² =Bu) (90 mg, 94%) identical withthat described above.

EXAMPLE 30(1R*,4S*)-3-Butyl-4-(dimethyl-t-butylsilyloxy)cyclopent-2-en-1-ol((±)-10; R¹ =Me₂ Bu^(t) Si, R² =Bu)

Lithium tri-s-butylborohydride in tetrahydrofuran (1 M, 0.5 ml, 0.5mmol) was added dropwise with vigorous stirring to the enone ((±)-9; R¹=Me₂ Bu^(t) Si, R² =Bu) (60 mg, 0.223 mmol) in tetrahydrofuran (0.5 ml)at -78°. After 2 h at this temperature water (1 ml) was added and themixture allowed to warm to room temperature. Dilution with water (5 ml)and extraction with ether (5×8 ml) gave, after drying (MgSO₄) andevaporation of the extracts, a colourless oil (155 mg). Preparativelayer chromatography on silica gel in methylene dichloride-methanol(50:1) yielded the (1R*,4S*)-alcohol ((±)-10; R¹ =Me₂ Bu^(t) Si, R² =Bu)(56 mg, 93%) as a colourless oil (Found: C, 66.7; H, 11.3. C₁₅ H₃₀ O₂ Sirequires C, 66.6; H, 11.2%).

EXAMPLE 31 (1S*,4R*)-2-Butyl-1-(dimethyl-t-butylsilyloxy)-4-(tetrahydropyran-2-yloxy)cyclopent-2-ene((±)-11; R¹ =Me₂ Bu^(t) Si, R² =Bu, R³ =Thp)

Dihydropyran (16.8 mg, 0.2 mmol) was added dropwise to the(1R*,4S*)-alcohol ((±)-10; R¹ =Me₂ Bu^(t) Si, R² =Bu) (40 mg, 0.15 mmol)in methylene dichloride (1 ml) containing p-toluenesulphonic acid (0.01M) at 0°. After 3 h the solution was diluted with ether (10 ml), washedsuccessively with 5% aqueous sodium bicarbonate (5 ml) and water (2×5ml), and dried (MgSO₄). Removal of the solvent under reduced pressureand chromatography of the residue (46 mg) on a column of silica gel (10g) in methylene dichloride-methanol (50:1) gave the (1S*,4R*)-diolderivative ((±)-11; R¹ =Me₂ Bu^(t) Si, R² =Bu, R³ =Thp) (39 mg, 73%) asa colourless liquid (Found: C, 67.6; H, 10.85. C₂₀ H₃₈ O₃ Si requires C,67.75; H, 10.8%).

EXAMPLE 32(1S*,4R*)-2-Butyl-4-(tetrahydropyran-2-yloxy)cyclopent-2-en-1-ol((±)-12; R² =Bu, R³ =Thp)

To the (1S*,4R*)-diol derivative ((±)-11; R¹ =Me₂ Bu^(t) Si, R² =Bu, R³=Thp) (24 mg, 0.068 mmol) in tetrahydrofuran (0.5 ml) at 0° was addedslowly tetrabutylammonium fluoride in tetrahydrofuran (0.5 M, 0.27 ml).After 2 h at 0° the solution was diluted with water (5 ml) and extractedwith ether (3×15 ml). The combined extracts were dried (MgSO₄),evaporated and the residual oil (40 mg) was chromatographed on a columnof silica gel (5 g) in light petroleum (b.p. 60°-80°)-ether (1:1) togive the (1S*,4R*)-alcohol ((±)-12; R² =Bu, R³ =Thp) (14 mg, 88%) as acolourless oil (Found: C, 69.65; H, 10.2. C₁₄ H₂₄ O₃ requires C, 69.95;H, 10.05%).

EXAMPLE 33 (4RS)-2-Butyl-4-(tetrahydropyran-2-yloxy)cyclopent-2-en-1-one ((±)-13; R² =Bu,R³ =Thp)

Pyridinium chlorochromate (12.9 mg, 0.06 mmol) was added to a suspensionof anhydrous sodium acetate (1 mg, 0.012 mmol) in methylene dichloride(0.3 ml) containing the (1S*,4R*)-alcohol ((±)-12; R² =Bu, R³ =Thp) (8mg, 0.033 mmol). After stirring at room temperature for 2 h the mixturewas diluted with ether (1 ml) and filtered through a pad of "Celite".Evaporation of the filtrate under reduced pressure and chromatographicpurification of the residual oil (10 mg) on silica gel (p.l.c.) inmethylene dichloride-methanol (50:1) gave the enone ((±)-13; R² =Bu, R³=Thp) (6.6 mg, 83%) as a colourless oil (Found: C, 70.55; H, 9.2. C₁₄H₂₂ O₃ requires C, 70.55; H, 9.3%).

EXAMPLE 34(1S*,4S*)-4-Benzoyloxy-1-(dimethyl-t-butylsilyloxy)-2-(6-ethoxycarbonylhexyl)cyclopent-2-ene((±)-20; R¹ =Me₂ Bu^(t) Si, R² =(CH₂)₆ CO₂ Et, R³ =COPh)

The (1R*,4S*)-alcohol ((±)-19; R¹ =Me₂ Bu^(t) Si, R² =(CH₂)₆ CO₂ Et) (37mg, 0.1 mmol), diethyl azodicarboxylate (34.8 mg, 0.2 mmol), triphenylphosphine (52.5 mg, 0.2 mmol) and benzoic acid (24.4 mg, 0.2 mmol) werestirred together in tetrahydrofuran (1 ml) for 20 h. Evaporation of thesolvent under reduced pressure gave a semi-crystalline residue which wastriturated with ether. Filtration, removal of solvent from the filtrateand preparative layer chromatography of the residual oil on silica gelin methylene dichloride (100%) gave the (1S*,4S*)-benzoate ((±)-20; R¹=Me₂ Bu^(t) Si, R² =(CH₂)₆ CO₂ Et, R³ =COPh) (44 mg, 93%) as acolourless oil (Found: C, 68.6; H, 8.55. C₂₇ H₄₂ O₅ Si requires C, 68.3;H, 8.9%).

EXAMPLE 35 (1S*,4S*)-4-(Dimethyl-t-butylsilyloxy)-2-(6-methoxycarbonylhexyl)cyclopent-2-en-1-ol((±)-20; R¹ =Me₂ Bu^(t) Si, R² =(CH₂)₆ CO₂ Me, R³ =H)

To the (1S*,4S*)-benzoate ((±)-20; R¹ =Me₂ Bu^(t) Si, R² =(CH₂)₆ CO₂ Et,R³ =CoPh) (32 mg, 0.067 mmol) in methanol (2 ml) was added aqueouspotassium carbonate (2%, 0.5 ml) and the mixture was stirred at roomtemperature. After 24 h solvent was removed under reduced pressure andthe residue was partitioned between water (5 ml) and ether (10 ml). Theaqueous phase was extracted with three further portions of ether (5 ml)and the combined ether extracts were washed with water (2×5 ml) beforedrying (MgSO₄). Preparative layer chromatography of the residual oil (32mg) on silica gel in methylene dichloride-methanol (50:1) gave the(1S*,4S*)-alcohol ((±)-20; R¹ =Me₂ Bu^(t) Si, R² =(CH₂)₆ CO₂ Me, R³ =H)(17 mg, 75%) as a colourless oil (Found: c, 64.15; H, 10.15. C₁₉ H₃₆ O₄Si requires C, 64.0; H, 10.2%).

EXAMPLE 36(1S*,4S*)-4-Benzoyloxy-1-(dimethyl-t-butylsilyloxy)-2-[7-(dimethyl-t-butylsilyoxy)heptyl]cyclopent-2-ene((±)-20; R¹ =Me₂ Bu^(t) Si, R² =(CH₂)₇ OSiMe₂ Bu^(t), R³ =COPh)

The (1R*,4S*)-alcohol ((±)-19; R¹ =Me₂ Bu^(t) Si, R² =(CH₂)₇ OSiMe₂Bu^(t)) (100 mg, 0.226 mmol), diethyl azodicarboxylate (71 ml, 0.45mmol), triphenylphosphine (118 mg, 0.45 mmol) and benzoic acid (55 mg,0.45 mmol) were stirred together in tetrahydrofuran (2 ml) for 20 h.Removal of the solvent and trituration of the residue with ether gave acrystalline residue which was removed by filtration. Evaporation of thefiltrate and preparative layer chromatography of the residue (425 mg) onsilica gel in methylene dichloride gave the (1S*,4S*)-benzoate ((±)-20;Me₂ Bu^(t) Si, R² =(CH₂)₇ OSiMe₂ Bu^(t), R³ =COPh) (112 mg, 91%) as acolourless oil (Found: c, 68.25; H, 9.85. C₃₁ H₅₄ O₄ Si₂ requires C,68.05; H, 9.95%).

EXAMPLE 37(1S*,4S*)-4-(Dimethyl-t-butylsilyloxy)-2-[7-(dimethyl-t-butylsilyoxy)heptyl]cyclopent-2-en-1-ol((±)-20; R² =Me₂ Bu^(t) Si, R² =(CH₂)₇ OSiMe₂ Bu^(t), R³ =H)

The (1S*,4S*) benzoate ((±)-20; R¹ =Me₂ Bu^(t) Si, R² =(CH₂)₇ OSiMe₂Bu^(t), R³ =COPh) (48 mg, 0.0877 mmol) was stirred with potassiumcarbonate (100 mg) in methanol (5 ml) for 4 h. After removal of thesolvent under reduced pressure the residue was extracted with ether (4×5ml) and the combined extracts were washed with water (2×5 ml), dried(MgSO₄) and evaporated to yield the (1S*,4S*)-alcohol ((±)-20; R¹ =Me₂Bu^(t) Si, R² =(CH₂)₇ OSiMe₂ Bu^(t), R³ =H) (36 mg, 93%) as achromatographically and spectroscopically pure oil (Found: M⁺, 442; M⁺-H₂ O, 424.3197. C₂₄ H₄₈ O₂ Si₂ requires M⁺, 442; M⁺ -H₂ O, 424.3193).

We claim:
 1. Compounds of the general formula I: ##STR19## wherein Arepresents O; R^(x) represents hydrogen or a removable alcoholprotecting group selected from the group consisting of substitutedsilyl, alkoxyalkyl, tetrahydrofuran-2-yl and tetrahydropyran-2-yl, andR^(y) represents halogen, an alkyl thio group, a dialkyl amino group, ora group of the formula R², and R² represents an unsubstituted straight-or branched-chain alkynyl group, or a straight- or branched-chainalkenyl or alkynyl group substituted by one or more carboxyl, carboxylicacid ester, or free or protected hydroxy, thiol, aldehyde or keto groupswherein the protected groups are selected from lower alkyl ethers andthio ethers, hydroxyl groups protected with substituted silyl,alkoxyalkyl, tetrahydrofuran-2-yl or tetrahydropyran-2-yl, non-cyclic orcyclic acetals and ketals and their thio analogues; with the provisothat R^(x) is not hydrogen when A is O and R^(y) is R².
 2. Compounds asclaimed in claim 1, wherein R^(x) represents a tri-substituted silylgroup wherein the substituents are selected from the group consisting ofalkyl, aryl and mixtures thereof.
 3. Compounds as claimed in claim 2,wherein R^(x) represents a dimethyl-t-butyl silyl group.
 4. Compounds asclaimed in claim 1, wherein R^(y) represents a chloro, bromo or iodogroup, or an alkyl-thio or di-alkyl amino group.
 5. Compounds as claimedin claim 1, wherein R^(y) represents an alkynyl group having up to 10carbon atoms.
 6. Compounds as claimed in claim 5, wherein said alkynylgroup has from 4 to 10 carbon atoms.
 7. Compounds as claimed in claim 5,wherein said alkynyl group is substituted by a dimethyl-t-butylsilyloxyor tetrahydropyran-2-yloxy group. 8.3-Chloro-4-hydroxycyclopent-2-en-1-one. 9.3-Chloro-4-(dimethyl-t-butylsilyloxy)-cyclopent-2-en-1-one.
 10. Acompound of the formula I: ##STR20## wherein R^(x) represents hydrogenor a removable alcohol protecting group selected from the groupconsisting of substituted silyl, alkoxyalkyl, tetrahydrofuran-2-yl andtetrahydropyran-2-yl; and R^(y) represents halogen, an alkyl thio groupor dialkyl amino group.
 11. A compound as claimed in claim 10, whereinR^(x) represents a tri-substituted silyl group wherein the substituentsare selected from the group consisting of alkyl, aryl and mixturesthereof.
 12. A compound as claimed in claim 11, wherein R^(x) representsa dimethyl-t-butyl silyl group.
 13. A compound as claimed in claim 10,wherein R^(y) represents a chloro, bromo or iodo group, or an alkyl-thioor di-alkyl amino group.
 14. A process for the preparation of compoundsof the general formula: ##STR21## wherein R^(x) represents hydrogen or aremovable alcohol protecting group selected from the group consisting ofsubstituted silyl, alkoxyalkyl, tetrahydrofuran-2-yl andtetrahydropyran-2-yl; and R^(y) represents halogen, an alkyl thio group,a dialkyl amino group, or a group of the formula R², and R² represents astraight- or branched-chain alkyl, alkenyl or alkynyl group which mayoptionally be substituted by one or more carboxyl, carboxylic acidester, or free or protected hydroxy, thiol, aldehyde or keto groups,wherein the protected groups are selected from lower alkyl ethers andthio ethers, hydroxyl groups protected with substituted silyl,alkoxyalkyl, tetrahydrofuran-2-yl or tetrahydropyran-2-yl, non-cyclic orcyclic acetals and ketals and their thio analogues; with the provisothat R^(x) is not hydrogen when R^(y) is R², said process comprising:(a)partial dehalogenation of a compound of the general formula II ##STR22##wherein Hal represents halogen, and R^(x) is as defined above, toproduce a compound of the general formula Ia: ##STR23## wherein Hal andR^(x) are as defined above; (b) protection of the hydroxyl substituentof a compound of the general formula Ia as defined above, in which R^(x)represents hydrogen to produce a compound of the general formula Ib;##STR24## wherein Hal is as defined above and R¹ represents a protectivegroup; (c) replacement of the halogen substituent of a compound of thegeneral formula Ib as defined above, to produce a compound of thegeneral formula Ic: ##STR25## wherein R⁴ represents a substituted thiogroup or a disubstituted amino group and R¹ represents a protectinggroup; and (d) reaction of a compound of the general formula Ib asdefined above or of a compound of the general formula Ic as definedabove in a conjugate addition-elimination reaction to produce a compoundof the general formula Id: ##STR26## wherein R¹ represents a protectinggroup and R² is as defined above.
 15. A process as claimed in claim 14,wherein said compound of the general formula II is prepared by oxidativedecarboxylation of a compound of the general formula IIa: ##STR27##wherein Hal represents halogen and R^(x) is as defined in claim
 14. 16.A process as claimed in claim 15, wherein said compound of the generalformula IIa is prepared by ring-contraction of phenol or2,4,6-trihalophenol with a halogen in the presence of an alkali.
 17. Aprocess as claimed in claim 14, further including the step of total orpartial resolution of a racemic mixture of a compound of the generalformula Ia, Ib, Ic, Id, or II.
 18. A process as claimed in claim 14,wherein said partial dehalogenation step is carried out in the presenceof a mild reducing agent.
 19. A process as claimed in claim 18, whereinsaid reducing agent comprises aqueous chromium (II) chloride.
 20. Aprocess as claimed in claim 14, wherein said step of protection of thehydroxyl substituent is carried out by reaction of the compound of thegeneral formula Ia with a compound of the formula R¹ X wherein R¹ is asdefined in claim 14, and X represents halogen.
 21. A process as claimedin claim 20, wherein said compound of formula R¹ X ischlorodimethyl-t-butylsilane.
 22. A process as claimed in claim 14,wherein an organomagnesium or organolithium reagent is used in saidconjugate addition-elimination reaction.
 23. A process as claimed inclaim 22, wherein said reagent is 7-(dimethyl-t-butylsilyloxy)heptylmagnesium bromide or 7-(tetrahydropyran-2-yloxy)heptyl magnesiumbromide.
 24. A process as defined in claim 15, further including thestep of total or partial resolution of a racemic mixture of a compoundof the general formula IIa.
 25. A process as defined in claim 14 furtherincluding total or partial inversion of the protected hydroxylsubstituent after at least one of the steps (a) through (d).
 26. Aprocess as defined in claim 15 including total or partial inversion ofthe hydroxyl or protected hydroxyl substituent.
 27. Compounds of thegeneral formula I: ##STR28## wherein A represents O; R^(x) representshydrogen or a removable alcohol protecting group selected from the groupconsisting of substituted silyl, alkoxyalkyl, tetrahydrofuran-2-yl andtetrahydropyran-2-yl; and R^(y) represents halogen, an alkyl thio group,a dialkyl amino group, or a group of the formula R², and R² represents astraight-or branched-chain alkynyl group which may optionally besubstituted by one or more carboxyl, carboxylic acid ester, or free orprotected hydroxy, thiol, aldehyde or keto groups wherein the protectedgroups are selected from lower alkyl ethers and thio ethers, hydroxylgroups protected with substituted silyl, alkoxyalkyl,tetrahydrofuran-2-yl or tetrahydropyran-2-yl, non-cyclic or cyclicacetals and ketals and their thio analogues; with the proviso that R^(x)is not hydrogen when A is O and R^(y) is R².